Retinitis pigmentosa (RP) is a group of inherited retinal disorders affecting rod photoreceptors, leading to blindness. Mechanisms responsible for RP are not understood; however, a number of mutations have been identified in retina-specific genes, including rhodopsin, suggesting that these mutations are responsible for the disease. Viral gene transfer techniques have been used to deliver corrective genes to animal models of RP. There is strong evidence that this mode of therapy will have great promise in the eye; however, success of the technique will depend upon tight regulation of transgene expression. Consequently, the long term goals of the proposed research are two4old: 1) to evaluate the efficiency of adeno-associated virus (AAV)-mediated retinal transgene expression using an exogenously regulatable tetracycline-based (TetOn) promoter system; and 2) to use an externally regulatable transgene system incorporated into AAV to attempt to rescue the retinal degeneration occurring in the rhodopsin knockout (RKO) mouse. For the first goal, the regulation of photoreceptor specific transgene expression will be evaluated in C57BI/6 mice, using the TetOn promoter system carrying the reporter gene green fluorescent protein (GFP). For rescue experiments, the appropriate AAVs carrying rhodopsin and the essential components of the TetOn system will be prepared and delivered to photoreceptors of the RKO mouse. Transgene expression will be modulated by administering and removing doxycycline from drinking water at different times, and transgene levels will be monitored by RNA analysis. Photoreceptor rescue will be assessed histologically.